A major public health issue in obesity is that obesity enhances the risk of developing type II diabetes and cardiovascular diseases. To reduce the prevalence of obesity, we need to understand the underlying mechanism of adipogenesis such that effective preventive and treatment strategies could be implemented to overcome these metabolic disorders. COUP-TFII is a member of the nuclear receptor superfamily and is highly expressed in mesenchymal cells during development. Ablation of COUP-TFII in mice results in early embryonic lethality due to defects in angiogenesis and heart development. During the course of analyzing the phenotypes of COUP-TFII heterozygous mice, we noted that the mutant mice are leaner and their adipose tissue mass is reduced in comparison to the control littermates. In addition, the abdominal white adipose tissues appear more like brown adipose tissues by expressing UCP-1, a marker of brown adipocytes important for adaptive thermogenesis. Consistent with the increase in brown fat-like tissues, the COUP-TFII heterozygous mutant is more insulin sensitive and glucose tolerant. Using 3T3L1cell culture models, we demonstrated that COUP-TFII is highly induced during the expansion phase of adipocyte differentiation. Knockdown of COUP-TFII expression during the early phase of 3T3L1 adipocyte differentiation disrupts the differentiation program and impairs the accumulation of triglycerides. These findings suggest that COUP-TFII is likely an important but yet unexplored regulator of adipocyte differentiation. To understand the role of COUP-TFII, we will use both tissue specific and conditional knockout as well as in vitro cell culture differentiation system to dissect COUP-TFII's role in adipogenesis. To accomplish these goals, three Specific Aims are proposed: Aim 1: Determine the in vivo role of COUP-TFII during adipogenesis;Aim 2: Investigate the mechanism by which COUP-TFII regulates adipocyte differentiation;Aim 3: Analyze COUP-TFII target genes in adipocytes. Our studies are timely and will reveal new information on COUP-TFII as a regulator of adipogenesis as well as provide additional targets for obesity intervention.